Lipoproteins have been found to have a number of influences on inflammation. The apo B-containing lipoproteins bind to monosodium urate crystals, the etiologic agent of gout, and are major, specific inhibitors of neutrophil responses to the crystals in vitro. The mechanism and structural requirements for the inhibitory effect of the predominant apo B lipoprotein, low density lipoprotein (LDL), will be analyzed. To establish the mechanism of LDL inhibition, its effects on physical association of neutrohils and crystals will first be evaluated using phase separation of crystal-cell suspensions in oils. Second, the effect of LDL on phagocytosis of the crystals will be quantitated and compared to concurrently measured effects on cytolysis. This will establish whether LDL acts by prevention of delivery of crystals to phagolysosomes or by inhibition of cytolysis, which is known to be initiated by phagolysosomal membranolysis. LDL effects on urate-induced membranolysis will also be directly addressed by quantitating 1) hemolysis of erythrocyte suspensions and 2) lactic dehydrogenase loss from neutrophils in the presence of cytochalasin B to block phagocytosis. Determination of the mechanism(s) responsible for LDL's effects will be followed by experiments to address the consequences of modifications of LDL structure. In this way, the structural requirements for lipoprotein inhibition of crystal-cell interaction will be ascertained. A number of LDL-related moieties will be evaluated: 1) LDL depleted of neutral lipids by starch-heptane extraction; 2) liposomes containing the major LDL lipids phosphatidyl choline, cholesterol and sphingomyelin at different molecular ratios; 3) core LDL and water soluble LDL peptides derived via limited digestion with trypsin and elastase, and 4) LDL modified by nonenzymatic glycosylation, acetylation and cationization. Modifications of LDL in this last fashion alter its high affinity apo B receptor-mediated cellular uptake and may inhibit or enhance cellular LDL degradation. The ability to bind to urate crystals will be quantitated, as a control, for each alteration of LDL which is associated with a loss of inhibitory activity for crystal-neutrophil interaction. These studies will address both the biologic effects of lipoproteins on neutrophil responses and the pathogenesis of crystal-induced inflammation and may point the way to a novel therapeutic approach.